There are approximately 34 million Americans at least 20 percent above their desirable weights for whom treatment is advisable, according to the conclusions reached by a recent NIH concensus conference. (National Institutes of Health consensus Panel Report, Feb. 13, 1985; See also Science, 1985, 207: 1019-1020.)
In these individuals obesity is a contributory factor to the increased incidence of cardiovascular disease, hypertension, hypercholesterolemia, non-insulin dependent diabetes (NIDD) and cancers of the uterus, breast, gallbladder, colon, rectum and prostate. In addition obesity has a negative weight related impact on mortality; such that in extreme or morbid obesity the mortality ratio may be 1200 percent above normal.
Weight reduction is often recommended as the first course of action for patients suffering from NIDD, hypertension, hypercholesterolemia, coronary artery heart disease, gout and osteoarthritis. However, there are relatively few therapeutic tools which the physician can use to accomplish weight loss. Pharmaceutical agents which are currently used as adjuncts to dietary counseling are effective for short term therapy, but are unacceptable for long term use because of the development of tolerance, their CNS activity and undesirable side effects. Thus, approximately 95% of those patients who successfully lose weight regain to their initial body weights within 12 to 84 months. An agent which reduces food intake by mimicking the body's own peripheral satiety signals would be expected to be more successful for use in chronic therapy, have a more desirable side effect profile and have less CNS activity.
Cholecystokinin (CCK) is a polypeptide hormone which was first isolated as a 33-amino acid peptide from the porcine gastrointestinal tract. (Mutt et al, Biochem J., 1971, 125: 57-58. Mutt et al., Clin Endocrinol, supplement, 1976, 5: 175-183.) Peripherally administered CCK has been shown to produce satiety in the rat and the monkey and infusions of CCK-8, the octapeptide analog of CCK, has been shown to decrease food intake in lean and obese men. G. P. Smith, Int J Obesity 1984, 8 Suppl 1:35-38: Jorpes et al, Acta. Chem. Scand, 1964, 18:2408; Della-Fera et al., Science, 1979, 206:471-73; Gibbs. et al., 1973, J. Comp. Physiology and Psychology, 84, 488-495. It is now accepted that CCK has satiety-inducing effects and thus., may be useful to reduce or suppress food intake in man.
The polypeptide hormone, CCK-33, has the amino acid sequence: ##STR1## Fragments of CCK, e.g. CCK-8 and CCK-7 also have been shown to have satiety-inducing effects. CCK-8 has the amino acid sequence: ##STR2## CCK-7 is one amino acid less than CCK-8, i.e., it is CCK-8 minus the 26-position Asp.
Various CCK-8 analogs are known. For example, U.S. Pat. No. 4,400,377 teaches the use of analogs of CCK-8 to treat pain. U.S. Pat. No. 4,490,364 discloses that analogs of CCK-8 stimulate the contraction of the gall bladder and assist the secretion of gastric acid. The psychodepressant use of CCK-8 analogs is disclosed by U.S. Pat. No. 4,517,180.
Although various analogs of CCK-8 are known, neither the CCK derivatives of the invention, nor their use to suppress food intake in animals is known. Further, although the naturally occurring peptides, CCK-33, CCK-8 and CCK-7 have satiety inducing effects, these peptides are short acting. Accordingly, it is an object of the invention to prepare CCK-analogs which exhibit satiety-inducing effects which are equal to or greater than the naturally occurring CCK-8 but which also have longer lasting effects.